The present invention relates to series of novel carbapenem compounds, and provides a process for preparing them and compositions containing them.
The carbapenem compounds have recently been developed as a potentially valuable series of antibiotics, and a variety of carbapenem compounds have been proposed for such use. The carbapenems are based upon the carbapenem nucleus, which may be represented by the following formula: ##STR2## Shown on the above formula is the numbering system commonly applied to such compounds. It can be seen that the carbapenems are structural analogs of the penicillins, in which the sulfur atom at the 1-position of the basic penicillin nucleus has been replaced by a carbon atom. The majority of carbapenem compounds have a carboxy group or a conventional derivative thereof (e.g. ester, salt or amide group) at the 3-position.
The present invention provides a limited class of compounds having, at their 2-positions, a particular selection of 1,2-disubstituted-4-pyrrolidinylthio groups.
Certain compounds similar to this are known. For example, Japanese Patent Application Kokai (i.e. laid upon to public inspection) No. 59-16892 discloses a group of compounds having, inter alia, a 1-hydroxyethyl group at the 6-position and, inter alia, a wide range of substituted pyrrolidinylthio groups at the 2-position. Likewise, European Patent Publication No. 126,587 discloses a class of penem compounds and their carbapenem analogs having, inter alia, a 1-hydroxyethyl group at the 6-position and a wide selection of substituted 4-pyrrolidinylthio groups at the 2-position. For example, amongst the compounds specifically disclosed in this European Patent Publication are the compounds 6-(1-hydroxyethyl)-2-(2-dimethylcarbamoyl-4-pyrrolidinylthio)-2-carbapenem -3-carboxylic acid and 6-(1-hydroxyethyl)-2-(2-carbamoyl-4-pyrrolidinylthio)-2-carbapenem-3-carbo xylic acid.
In U.S. patent application Ser. No. 714,373 filed 21 Mar. 1985, there is disclosed a class of carbapenem derivatives, some of which are similar to those of the present invention, but distinguished in that the prior compounds are characterized by the presence of at least one, and optionally two, substituents at the 1-carbapenem site.
We have now surprisingly found that a specific class of 6-(1-hydroxyethyl)-2-(1,2-disubstituted-4-pyrrolidinylthio)-2-carbapenem-3 -carboxylic acid derivatives in which the substituents at the 2-position of the pyrrolidinyl ring are chosen from a limited class of carboxy, carbamoyl, cyano and hydroxymethyl and related groups and in which the same compound also has at the 1-position of the pyrrolidinyl ring a limited class of imidoyl substituents combines both reduced renal toxicity and excellent bioavailability. Since undesirably high renal toxicity and limited bioavailability are two common disadvantages of the carbapenem group of compounds, these advantages of the compounds of the invention are expected to lead to exciting therapeutic possibilities.